PREVENTION OF GRAFT-VERSUS-HOST DISEASE IN MICE USING A SUICIDE GENE EXPRESSED IN T-LYMPHOCYTES

Alloreactive T cells present in a bone marrow transplant are responsib le for graft-versus-host disease (GVHD), but their depletion is associ ated with impaired engraftment, immunosuppression, and loss of the gra ft-versus-leukemia effect. We developed a therapeutic strategy against GVHD based on the selective destruction of these alloreactive T cells , while preserving a competent T-cell pool of donor origin, We generat ed transgenic mice expressing in their T lymphocytes the Herpes simple x type 1 thymidine kinase (TK) suicide gene that allows the destructio n of dividing T cells by a ganciclovir treatment. T cells expressing t he TK transgene were used to generate GVHD in irradiated bone marrow g rafted mice, We show that a short 7-day ganciclovir treatment, initiat ed at the time of bone marrow transplantation, efficiently prevented G VHD in mice receiving TK-expressing T cells. These mice were healthy a nd had a normal survival, They maintained a T-cell pool of donor origi n that responded normally to in vitro stimulation with mitogens or thi rd party alloantigens, but were tolerant to recipient alloantigens. Ou r experimental system provides the proof of concept for a therapeutic strategy of GVHD prevention using genetically engineered T cells. (C) 1997 by The American Society of Hematology.